While current anti-retroviral drug regimens have elicited improved marker and clinical responses in patients infected with HIV-1 infection, treatment failures related to drug resistance remain on ongoing challenge. Consequently, HIV-1 therapies are still requires which prevent or delay the emergence of resistance to co-administered agents, and/or which retain anti-viral effects in patients with extensive anti-retroviral experience. To this end, in preliminary studies, we established that genetic antivirals targeting the HIV-1 Rev regulatory system inhibited standard laboratory HIV-1 strains as well as B subtype clinical isolates with high level resistance to multiple anti-retroviral drugs. This suggests a potential role for gene therapy as primary or adjuvant treatment for patients failing standard HIV-1 chemotherapeutic regimens. This project will further examine the molecular interplay and potential therapeutic utility of combined genetic and chemotherapeutic antivirals for the treatment of HIV-1 infection. Two basic combination strategies will be studied. First, the in vitro HIV-1 inhibitory and resistance characteristics of combined genetic and chemotherapeutic anti-retroviral agents targeted at divergent steps of viral replication will be studied. Anti-Rev system genetic elements will be used in concert with chemotherapeutic reverse transcriptase inhibitors to assess changes in vitro anti-viral activity relative to standard chemotherapy. Resulting phenotypic and genotypic resistance patterns will also be evaluated. In a second strategy, genetic antivirals directed against pivotal HIV-1 drug resistant genotypes will be combined with anti-retroviral drugs in an attempt to prevent and/or treat the emergence of HIV-1 drug resistance. More specifically, antisense RNA directed against HIV-1 nucleoside analog reverse transcriptase inhibitor resistance genotypes will be combined with nucleoside analogs to assess whether anti-viral potency and durability are expanded through the genetically-mediated disruption of typical drug resistance patterns. Changes in baseline phenotypic resistance will also be measured by drug susceptibility assays, and the selection of alternative resistance mutations will be characterized by standard viral genotyping protocols. HIV-1 continues to demonstrate an ability to escape current anti-retroviral regimens. Combining anti-HIV-1 genetical elements with the expanding repertoire of HIV-1 chemotherapeutic agents offers a promising new strategy for the long term inhibition of viral replication and treatment and/or prevention of multidrug resistance.